title: The transcription factor HNF1α induces expression of angiotensin-converting enzyme 2 (ACE2) in pancreatic islets from evolutionarily conserved promoter motifs.
abstract: Pancreatic angiotensin-converting enzyme 2 (ACE2) has previously been shown to be critical for maintaining glycemia and β-cell function. Efforts to maintain or increase ACE2 expression in pancreatic β-cells might therefore have therapeutic potential for treating diabetes. In our study, we investigated the transcriptional role of hepatocyte nuclear factor 1α (HNF1α) and hepatocyte nuclear factor 1β (HNF1β) in induction of ACE2 expression in insulin-secreting cells. A deficient allele of HNF1α or HNF1β causes maturity-onset diabetes of the young (MODY) types 3 and 5, respectively, in humans. We found that ACE2 is primarily transcribed from the proximal part of the ACE2 promoter in the pancreas. In the proximal part of the human ACE2 promoter, we further identified three functional HNF1 binding sites, as they have binding affinity for HNF1α and HNF1β and are required for induction of promoter activity by HNF1β in insulinoma cells. These three sites are well-conserved among mammalian species. Both HNF1α and HNF1β induce expression of ACE2 mRNA and lead to elevated levels of ACE2 protein and ACE2 enzymatic activity in insulinoma cells. Furthermore, HNF1α dose-dependently increases ACE2 expression in primary pancreatic islet cells. We conclude that HNF1α can induce the expression of ACE2 in pancreatic islet cells via evolutionarily conserved HNF1 binding sites in the ACE2 promoter. Potential therapeutics aimed at counteracting functional HNF1α depletion in diabetes and MODY3 will thus have ACE2 induction in pancreatic islets as a likely beneficial effect.
authors.affiliation: Department of Pharmacology & Experimental Therapeutics and Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, 1901 Perdido St., New Orleans, LA 70112, USA.
authors.forename: Kim Brint
authors.initials: KB
authors.lastname: Pedersen
authors.forename: Kavaljit H
authors.initials: KH
authors.lastname: Chhabra
authors.forename: Van K
authors.initials: VK
authors.lastname: Nguyen
authors.forename: Huijing
authors.initials: H
authors.lastname: Xia
authors.forename: Eric
authors.initials: E
authors.lastname: Lazartigues
mesh_terms: D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D019143:Evolution, Molecular; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000502:physiology*; D006801:Humans; D007515:Islets of Langerhans / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2
keywords: 7-(Methoxycoumarin-4-yl)acetyl-Ala-Pro-Lys(2,4-Dinitrophenyl)-OH; ACE2; Ang; C(t); DPT; HNF1α; HNF1β; MODY; MOI; Mca-APK(Dnp); PPT; Pancreatic islets; Promoter; RAS; RLU; Renin angiotensin system; Transcriptional regulation; angiotensin; angiotensin-converting enzyme 2; cycle-threshold; distal promoter transcripts; eGFP; enhanced green fluorescent protein; hepatocyte nuclear factor 1α; hepatocyte nuclear factor 1β; maturity-onset diabetes of the young; multiplicity of infection; proximal promoter transcripts; relative light units; renin-angiotensin system